chapter  12
34 Pages

Chapter Site-Specic Prodrug Activation Strategies for Targeted Drug Action

The prodrug concept, as rst introduced by Albert, dened a prodrug as a biologically inactive agent that is converted in vivo through enzymatic and/or chemical reactions to a therapeutically active drug.1 Traditionally, prodrugs are used in the pharmaceutical industry when the active drug exhibits limitations in either its pharmaceutical properties (e.g., solubility, taste, stability) or its pharmacokinetic prole (e.g., oral bioavailability, half-life).2 The successful application of prodrug strategies over the past two decades has increased the percentage of drugs gaining approval as prodrugs to 5%–7%3 and has spurred efforts to discover new strategies.4,5

A less well developed application of the prodrug concept entails the use of prodrugs for site-specic drug delivery.6 Targeting drugs to pathophysiologically relevant sites represents an attractive strategy for simultaneously optimizing the efcacy and safety proles of drug candidates.7 Historically, site-specic drug delivery is achieved using local drug administration strategies8 or drug conjugate strategies, wherein the drug is attached to a macromolecular carrier that recognizes organ-specic markers (e.g., antigens and receptors). In some cases, the markers are expressed on the surface of the vascular endothelium9,10 and, therefore, require cleavage of the drug conjugate by enzymes circulating in the blood or on the surface of the endothelium prior to distribution of the drug into the target tissue (Figure 12.1, path a). The distribution of the drug into the target tissue requires the uptake to be signicantly faster than the rate of drug removal from the local site via the circulation.